Synthesis of amino-1,4-benzoquinones and their use in Diels - Alder approaches to the aminonaphthoquinone antibiotics

Article abstract of DOI:10.1021/jo201320g

A new protocol for the synthesis of protected amino-1,4-benzoquinones by oxidation of the corresponding 2,5-dimethoxyaniline derivatives using PhI(OAc)₂ or PhI- (OCOCF₃)₂ in water containing 2.5% methanol is reported. The process represents an improvement over previously reported methods, both in terms of yield and number of steps, and in the range of nitrogen protecting groups that it tolerates. A number of novel aminobenzoquinones were prepared and subsequently used as dienophiles in Diels - Alder reactions to (Figure presented) form building blocks for the synthesis of the aminonaphthoquinone antibiotics such as salinisporamycin.

Full text of DOI:10.1021/jo201320g

ARTICLE
pubs.acs.org/joc
Synthesis of Amino-1,4-benzoquinones and Their Use in DielsÀAlder
Approaches to the Aminonaphthoquinone Antibiotics
Christopher C. Nawrat, William Lewis, and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
S Supporting Information
b
ABSTRACT: A new protocol for the synthesis of protected
amino-1,4-benzoquinones by oxidation of the corresponding
2,5-dimethoxyaniline derivatives using PhI(OAc)2 or PhI-
(OCOCF3)2 in water containing 2.5% methanol is reported.
The process represents an improvement over previously re-
ported methods, both in terms of yield and number of steps, and
in the range of nitrogen protecting groups that it tolerates. A
number of novel aminobenzoquinones were prepared and
subsequently used as dienophiles in DielsÀAlder reactions to
form building blocks for the synthesis of the aminonaphthoquinone antibiotics such as salinisporamycin.
’ INTRODUCTION
Aminonaphthoquinones are found at the core of a number of
commercially and biologically important natural products and
their derivatives (Figure 1).1 Rifabutin, a semisynthetic derivative
of rifamycin S (1), is a current frontline treatment for
tuberculosis,2,3 and other members of this family show various
biological activities. The recently isolated natural product
salinisporamycin (2) also shows promising antibacterial and
anticancer properties.4
Our ongoing interest in the synthesis of naturally occurring
quinones,5À9 and in particular the Cdc25A inhibitor 3,10
prompted consideration of a range of routes to such amino-
naphthoquinones. One particularly attractive approach is the
DielsÀAlder reaction of electron rich dienes with protected
aminobenzoquinones (Scheme 1A) because it reduces the need
for excessive classical manipulation of the aromatic naphthalene
ring system, as found in many older syntheses of natural products
of this type. However, this is a surprisingly underused tactic,
possibly because preparation of the quinone dienophile is not
Figure 1. Some naturally occurring aminonaphthoquinones.
straightforward due to the fact that oxidation of electron rich
anilines and anilides is often plagued by side reactions and only
fully aromatic product in good yield. The role of the halogen atom
was thought to be crucial in directing the regiochemical course of
the cycloaddition in addition to facilitating aromatization.
Interestingly, more than two decades later, a report from the
Nicolaou laboratory showed that the simple unhalogenated
2-acetamidobenzoquinone 9 reacted with the Danishefsky diene
8 to give, after aerial oxidation, a single product, the naphtho-
quinone 10 (Scheme 1C).12 This outcome was rationalized
by the observation that the product 10 simply resulted from
attack of the most nucleophilic end of the diene with the more
tolerates a very narrow range of protecting groups, which can
complicate synthetic operations after the DielsÀAlder reaction.
Also, as far as we aware, the regiochemical outcome of DielsÀ
Alder reactions involving aminobenzoquinones has never been
systematically studied despite the fact that control of regiochem-
istry would be essential if the reaction were to be used in
synthesis. Hence, there is but one example of this reaction being
applied in natural product synthesis, in Kelly and co-workers’
approach to the tricyclic core of the rifamycins.11 In this synthesis
of the rifamycin core 7, the DielsÀAlder reaction between the
electron rich diene 4 and 6-halo-2-acetamidobenzoquinones 5
and 6 gave a single naphthoquinone regioisomer (Scheme 1B).
Acidic workup assisted the loss of methanol and HX to give the
Received: June 23, 2011
Published: August 25, 2011
r
2011 American Chemical Society
7872
dx.doi.org/10.1021/jo201320g J. Org. Chem. 2011, 76, 7872–7881
|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. (A) The DielsÀAlder Disconnection of Amino-
naphthoquinones, (B) Use of 6-Halo-2-acetamidobenzo-
quinones, (C) Use of 2-Acetamidobenzoquinone
Table 1. Oxidation of 2,5-Dimethoxyaniline Derivatives to
2-Aminobenzoquinonesa
entry
X
Pg
R
quinone
yield/%
1
2
3
4
5
6
7
H
Ac
Me
9
73b
56
75
68
53
66
73
H
Boc
Bz
Me
11
12
13
14
15
16
H
Me
Cl
Br
Cl
Cl
Ac
CF3
CF3
CF3
CF3
Ac
Boc
Bz
a All reactions performed on protected aniline (1 mmol) using PhI-
(OAc)2 (2.0À2.5 equiv), H2OÀMeOH, rt, 2 h, or PhI(OCOCF3)2
(1.2À1.5 equiv), H2OÀMeOH, rt, 0.5À2 h. b Essentially identical yield
obtained on 10 g (50 mmol) scale.
reported, although again only for acetamides.15 The shortest, if
not the most practical, route to this class of compounds was
published in 2002 when the Nicolaou group reported the
remarkable oxidation of acetanilide into acetamidobenzoquinone
in a single step, using the DessÀMartin peridiodinane in
dichloromethaneÀwater.16À18 A yield of 43% was reported for
this step, which is impressive for the transformation accom-
plished. However, 4 equiv of the oxidant were required and
commercial DessÀMartin periodinane is expensive. Further-
more, when we attempted to apply these conditions to a larger
range of substrates, we found the reaction to be very sensitive to
the nature of the nitrogen protecting group, often resulting in
much lower yields. We therefore soughtto developa more general
and practical procedure for the preparation of these compounds.
In 2001, Kita and co-workers reported an efficient method for
conversion of 1,2,4-trimethoxybenzene into 2-methoxy-1,4-ben-
zoquinone using 1.2 equiv of inexpensive PhI(OAc)2 as oxidant
in water containing a small amount of methanol.19 It is worth
noting that this transformation is difficult using conventional
methods; CAN gave only a very low yield of dimerized products
and AgOÀHNO3 only caused degradation. Given the success of
this method in oxidizing such an electron rich system, we applied
these conditions to 2,5-dimethoxacetanilide. After optimization
of stoichiometry and concentration, we were able to obtain the
corresponding quinone 9 in a good yield simply by stirring
2,5-dimethoxacetanilide with 2 equiv of PhI(OAc)2 in waterÀ
methanol (97.5À2.5) in an open flask for two hours. With this
result in hand, we applied the same conditions to a range of
protected anilines to test the scope of this transformation
(Table 1). Thus the Boc- and benzoyl-protected aminobenzoqui-
nones 11 and 12 were similarly prepared in good yield (Table 1).
electrophilic position on the dienophile (i.e., the position 1,4 to
the carbonyl not deactivated by the amide-type resonance shown
in Scheme 1C). This result was significant as it meant that the
“directing” halogen thought to be essential by Kelly and co-
workers could be dispensed with, as it was not required to control
the regiochemical outcome of the DielsÀAlder reaction, nor to
facilitate the aromatization step. We therefore set out to explore
the use of simple aminobenzoquinones such as 9 in approaches
to naturally occurring aminonaphthoquinones and also to com-
pare the reactivity of 5-halo-2-aminobenzoquinones in DielsÀ
Alder reactions with their 6-halo isomers (cf. Scheme 1B).
However, at the outset, there was no general method suitable
for the preparation of the range of benzoquinones required for
our studies, and therefore this became our initial priority.
’ RESULTS AND DISCUSSION
Few aminobenzoquinones are reported in the literature, the
most common being 2-acetamido-1,4-benzoquinone (9). There
is a single report of the direct oxidation of 2,5-dimethoxyaceta-
nilide into the corresponding quinone 9,13 but the method uses
8 equiv of cerium(IV) ammonium nitrate (CAN) under dilute
conditions and therefore would not be suitable for preparing
larger amounts of material. Syntheses that start from such
compounds have therefore relied on variations of a two-step
protocol whereby dimethoxyacetanilide is first demethylated
using boron tribromide and the resulting hydroquinone is then
oxidized.14 Although yields over two steps are often reasonable,
the choice of aniline protecting group is limited to the fairly
narrow subset that is stable to strong Lewis acids, and this very
property may complicate deprotection later in the synthesis.
Oxidation to the quinone monoketal under anhydrous condi-
tions, followed by a separate acid hydrolysis step, has also been
In addition to the protected aminoquinones 9, 11, and 12, a
number of halogenated quinones were also prepared by oxida-
tion of the corresponding 2,5-dimethoxyaniline derivatives.
These substrates were easily prepared by protection of commer-
cially availably 4-chloro-2,5-dimethoxyaniline or by bromination
of 2,5-dimethoxyacetanilide. It should be noted that prepara-
tion of haloaminobenzoquinones is generally somewhat easier
than the preparation of the corresponding unhalogenated qui-
nones because the halogen atom serves to block the main site of
7873
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
Scheme 2. A DielsÀAlder Approach to the Aminonaphtho-
Scheme 3. Synthesis of the Aminonaphthoquinone Core 17
of Salinisporamycin and its Regioisomer 22
quinone Core of Salinisporamycin
dimerization in these molecules and reduce side reactions.
Interestingly, it was found that that PhI(OCOCF3)2 was a much
better oxidant for the preparation of haloquinones, giving higher
yields and shorter reaction times than PhI(OAc)2 in all cases.
In contrast, PhI(OAc)2 remains a superior oxidant for unhalo-
genated compounds. It is also noted that there is a requirement
for both an electron withdrawing N-protecting group and an
NH bond. 2,5-Dimethoxyanilines bearing NMeBoc or NMeBz
groups are inert to the above oxidizing conditions, even after
several days. Similarly, a number of di-Boc-protected 2,5-di-
methoxyanilines were prepared and also failed to undergo the
desired oxidation. This observation is consistent with a mecha-
nism in which the first step is formation of a covalent bond to the
oxidant, through the amide oxygen, followed by generation of an
ortho-azaquinone, as has been proposed for similar systems.12,20
With a range of protected aminobenzoquinones in hand, we
investigated their utility in the synthesis of building blocks of
naphthoquinone natural products, starting with consideration
of the recently isolated antibiotic salinosporamycin (Scheme 2).4
We envisaged that the aminonaphthoquinone core 17 of this
natural product could arise from the DielsÀAlder reaction
between known diene 1921 and a suitably protected aminoben-
zoquinone. On the basis of the precedent discussed above it, was
assumed that in the absence of a halogen, the regioselectivity
observed in Scheme 1C would prevail.
Thus, diene 19 was reacted with Boc-protected aminobenzo-
quinone 11 in toluene in room temperature to give, after aromati-
zation and aerial oxidation, naphthoquinone 20 (Scheme 3).
Disappointingly, elimination of methanol had not occurred
during the aromatization, and thus a methoxy group was present
in place of the expected hydroxyl at the 8-position. Addition of
bases (pyridine, NEt3, i-Pr2NEt) did not promote the desired
elimination nor did the strongly acidic workup described by Kelly
and co-workers in their studies toward the rifamycin core.11
Interestingly, use of 6-chloro-2-tert-butoxycarbonylamino-1,4-
benzoquinone (prepared in low yield from tert-butyl 3,5-di-
chloro-2-hydroxyphenyl carbamate) did give predominantly
the corresponding 6,8-dihydroxynaphthoquinone 18 along with
small amounts of 20, but we wished to avoid the extra steps and
poor yields associated with the preparation of this dienophile.
Importantly, although the presence of the methoxy group in
naphthoquinone 20 was unplanned, it proved inconsequential
because it was readily cleaved along with the Boc group in a single
step. Thus heating compound 20 with excess MgBr2 under reflux
in toluene gave the desired core naphthoquinone 17, the core
chromophore of salinisporamycin, in excellent yield (Scheme 3).
The regiochemical outcome of the DielsÀAlder reaction
could not be unambiguously determined by NMR spectroscopy,
and unfortunately neither of the naphthoquinones 17 or 20 gave
crystals suitable for X-ray analysis. Therefore, to assist in con-
firming the structure of 17, we sought to prepare the 3-amino
regioisomer 22 for comparison. In the 1980s, Brassard and co-
workers showed that regioselectivity in the DielsÀAlder reaction
of benzoquinone derivatives could be controlled by the position
of a halogen on the quinone dienophile,22 the more nucleophilic
end of the diene reacting with the unhalogenated position on the
benzoquinone. However, none of the quinones used in this study
displayed the strong regiochemical preference exhibited by our
2-amino-1,4-benzoquinones in the absence of a halogen. We
were therefore curious to see if blocking the position para to the
nitrogen using a halogen atom could overturn the observed
regioselectivity of the DielsÀAlder reaction that gave exclusively
naphthoquinone 20 and hence allow access to the regioisomeric
product. Thus, when the reaction was repeated using the
5-chloro-2-aminobenzoquinone derivative 15 as the dienophile,
a single regioisomeric product 21 was again obtained which, after
deprotection gave the aminonaphthoquinone 22. The 13C NMR
spectra of the two regioisomers 17 and 22 were clearly different,
although their 1H NMR spectra were very similar, except the peri
hydroxyl protons. In the undesired 3-amino isomer 22, the peak
corresponding to this proton is observed at 13.71 ppm, due to the
strong hydrogen bond with the peri carbonyl, the Lewis basicity
of which is increased by donation from the nitrogen lone pair
(this carbonyl can be regarded as a vinylogous amide). In the
desired 2-amino regioisomer 17, where this mesomeric donation
is absent, this proton is observed at 12.22 ppm. Thus, by having
access to both regioisomers, the regiochemistry can be inferred
from the dramatic difference in the chemical shift of this proton
in the 1H NMR spectra.
Thus we have confirmed that the natural regiochemical
preference of 2-aminobenzoquinones in DielsÀAlder reactions
with appropriate electron rich dienes results in formation of a
2-aminonaphthoquinone derivative (cf. Scheme 1C) and that the
presence of a 6-halogen substituent in the dienophile
(cf. Scheme 1B) is not required to achieve this regiospecificity.
On the other hand, this DielsÀAlder regiochemistry can be
completely overridden by the introduction of a 5-halogen sub-
stituent into the dienophile.
7874
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
Scheme 4. DielsÀAlder Adducts for the Synthesis of the
conjugate addition of transoid dienes to 2- and 3-bromo-5-
hydroxy-1,4-naphthoquinones showed essentially no difference
in LUMO coefficients for the C-2 and C-3 atoms for either system
despite the fact that a very strong preference for addition to the
unhalogenated carbon was observed.24 Our own preliminary
calculations on 13 again indicate only an insignificant difference
between the LUMO coefficients of C-5 and C-6 (and also the
coefficients of these atoms in 9) that cannot explain the extremely
high levels of regioselectivity observed.
Aminonaphthoquinone Core of the Cdc25A Inhibitor 3
’ CONCLUSION
In conclusion, we have demonstrated that iodine(III) reagents
are uniquely suitable for the oxidation of a range of protected
2,5-dimethoxyanilines to the corresponding 2-aminobenzoqui-
nones. The method is convenient, rapid, operationally simple,
uses inexpensive organic oxidants, and is amenable to use on
multigram scale. A range of nitrogen protecting groups are
tolerated giving access to a number of novel aminobenzoquinones
that were subsequently used in highly regioselective DielsÀAlder
reactions to give aminonaphthoquinones. This method for the
preparation of 2-aminonaphthoquinones such as 17 also obviates
the problem of introducing the amino functionality into an
existing quinone, classically performed by displacement of a
suitable leaving group with ammonia in a sealed tube. Impor-
tantly, the regiochemical outcome of the DielsÀAlder reaction is
completely controlled by the presence, or absence, of a 5-halogen
substituent on the 2-aminobenzoquinone dienophile, hence giv-
ing selective access to 2- or 3-aminonaphthoquinones as building
blocks for the synthesis of the aminonaphthoquinone antibiotics.
To further demonstrate the ability of a halogen atom to control
the regiochemical outcome of quinone DielsÀAlder reactions, we
investigated application of this methodology to the synthesis of a
3-aminonaphthoquinone precursor to the Cdc25A inhibitor 3,
previously inaccessible by known DielsÀAlder chemistry. The
diene required for such an approach has to contain suitable
masked functionality to develop into the final pyran ring later in
the synthesis, and therefore the new dioxolane containing diene
24 was prepared as shown in Scheme 4. Following monoprotec-
tion of acetylacetone as its mono ketal,23 olefination gave 23 as an
inconsequential mixture of geometric isomers, and treatment of
this ester with LDA and TMSCl gave the diene 24, the reaction
being readily conducted on a 20 g scale. Reaction of this diene
with the Boc-protected aminobenzoquinone11 gave the expected
2-aminonaphthoquinone derivative 25, with the incorrect regio-
chemistry for a synthesis of 3. However, as planned, the introduc-
tion of a halogen into the quinone dienophile reversed the
regioselectivity of the DielsÀAlder reaction. Thus reaction of
diene 24 with the chlorobenzoquinone 15 gave the regioisomeric
3-aminonaphthoquinone derivative 26 (Scheme 4), the structure
of which was confirmed by X-ray crystallography (see Supporting
Information), and is a potential precursor to the naturally
occurring pyranonaphthoquinone 3. Likewise, 2-acetamido-5-
chlorobenzoquinone 13 gave regioselectively the corresponding
3-acetamidonaphthoquinone 27 (Scheme 4). Although the struc-
ture of naphthoquinone 26 was confirmed unambiguously using
X-ray crystallography, there is again a very large difference in the
chemical shift of the 8-hydroxy proton in the otherwise very
similar 1H NMR spectra of the two regioisomers 25 (δ11.38) and
26 (δ12.32), which allows their rapid differentiation.
’ EXPERIMENTAL SECTION
General Experimental Details. Commercially available reagents
were used throughout without purification unless otherwise stated.
Anhydrous solvents were used as supplied unless otherwise stated.
Tetrahydrofuran was distilled from sodium benzophenone ketyl under
nitrogen atmosphere. Dichloromethane was distilled from calcium
hydride under a nitrogen atmosphere. Light petroleum refers to the
fraction with bp 40À60 °C. Ether refers to diethyl ether. Reactions were
routinely carried out under a nitrogen or argon atmosphere. Analytical
thin layer chromatography was carried out on aluminum backed plates
coated with silica gel and visualized under UV light at 254 and/or 360 nm
and/or potassium permanganate or ethanolic vanillin dip. Chromatog-
raphy was carried out on silica gel. Fully characterized compounds were
chromatographically homogeneous. Infrared spectra were recorded in
the range 4000À600 cmÀ1 as solutions in chloroform or as a solid in
attenuated total reflectance (ATR) mode. NMR spectra were recorded
NMR spectra were recorded at the frequencies stated. Chemical shifts are
quoted in ppm and J values in Hz. Chemical shift values are referenced
against residual proton in the deuterated solvents. In the 13C NMR
spectra, signals corresponding to CH, CH2, or CH3 are assigned from
DEPT-90 and -135 spectra; all others are quaternary C. High and low
resolution mass spectra were recorded on a time-of-flight spectrometer.
N-(2,5-Dimethoxyphenyl)acetamide
The origin of the ability of halogen atoms to direct DielsÀAlder
reactions of benzoquinone dienophiles, although known for more
than two decades, remains obscure. Ab initio calculations per-
formed by Grunwell and co-workers in their investigation of
Acetyl chloride (11.13 mL, 156.68 mmol) was added to a solution
of 2,5-dimethoxyaniline (20.0 g, 130.57 mmol) and triethylamine
7875
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
(21.75 mL, 156.68 mmol) in dichloromethane (500 mL) at 0 °C.
The resulting solution was warmed to rt over 30 min and then
washed with water (3 Â 100 mL), saturated aqueous sodium hydrogen
carbonate solution (200 mL) and brine (200 mL), and then dried
(MgSO4) and concentrated to give the title compound as a brown
crystalline solid (24.19 g, 95%) that did not require further purification;
mp 88À89 °C (lit.,25 mp 91À92 °C). (Found: C, 61.3; H, 6.7; N,
7.2%. C10H13NO3 requires C, 61.5; H, 6.7; N, 7.2%.). (Found: [M +
N-(4-Chloro-2,5-dimethoxyphenyl)acetamide
Acetyl chloride (0.91 mL, 12.79 mmol) was added to a solution of
4-chloro-2,5-dimethoxyaniline (2.0 g, 10.66 mmol) and triethylamine
(1.78 mL, 12.79 mmol) in dichloromethane (50 mL) at 0 °C. The brown
solution was warmed to rt over 30 min and poured into water (100 mL).
The layers were separated, and the aqueous phase was extracted
with dichloromethane (3 Â 50 mL). The combined extracts were
washed with water (100 mL) and brine (100 mL), dried (MgSO4),
and concentrated to a brown crystalline solid (2.31 g, 95%) that did
not require further purification; mp 116À117 °C (lit.,27 mp 118 °C).
(Found: C, 52.2; H, 5.3; N, 5.9%. C10H12ClNO3 requires C, 52.3; H,
+
Na+], 218.0784. C10H13NNaO3 requires 218.0788.) νmax (CHCl3)/
cmÀ1 3426, 3011, 1688, 1601, 1531, 1479, 1425, 1240, 1046. δH
(400 MHz; CDCl3) 8.12 (1 H, d, J 3.2), 7.81 (1 H, s), 6.80 (1 H, d,
J 9.0), 6.60 (1 H, dd, J 3.2, 9.0), 3.86 (3 H, s), 3.80 (3 H, s) 2.22 (3 H,
s). δC (100 MHz; CDCl3) 168.2 (C), 153.9 (C), 141.8 (C), 128.4
(C), 110.6 (C), 108.3 (CH), 106.0 (CH), 56.2 (Me), 55.8 (Me),
25.0 (Me).
tert-Butyl 2,5-Dimethoxyphenylcarbamate
5.3; N, 6.1%.) (Found: [M + Na+], 252.0402. C10H1235ClNNaO3
+
requires 252.0398.) νmax (CHCl3)/cmÀ1 3426, 3011, 1689, 1597, 1521,
1483, 1465, 1450, 1401, 1244, 1038. δH (300 MHz; CDCl3) 9.25 (1 H,
s), 7.75 (1 H, br s), 6.89 (1 H, s), 3.89 (3 H, s), 3.85 (3 H, s), 2.21 (3 H,
s). δC (75 MHz; CDCl3) 168.3 (C), 149.1 (C), 141.6 (C), 127.1 (C),
115.5 (C), 112.2 (CH), 104.8 (CH), 56.7 (Me), 56.3 (Me), 25.0 (Me).
N-(4-Bromo-2,5-dimethoxyphenyl)acetamide
Di-tert-butyl dicarbonate (8.55 g, 39.2 mmol) was added to 2,5-
dimethoxyaniline (5.0 g, 32.6 mmol) in THF (20 mL), and the resulting
solution was heated to reflux and stirred for 16 h and then cooled to rt
and concentrated. The residue was purified by flash column chroma-
tography on silica gel eluting with ethyl acetateÀlight petroleum (1:20)
to give the title compound as a colorless oil (7.51 g, 91%). (Found: C,
61.5; H, 7.6; N, 5.3%. C13H19NO4 requires C, 61.6; H, 7.6; N, 5.5%.)
+
(Found: [M + Na+], 276.1211. C13H19NNaO4 requires 276.1206.)
Bromine (0.55 mL, 10.76 mmol) in dichloromethane (5 mL) was
added dropwise to 2,5-dimethoxyacetanilide (2.0 g, 10.24 mmol) in
dichloromethane (50 mL) at rt. The brown solution was stirred for 6 h
and then washed with saturated aqueous sodium thiosulfate solution
(50 mL), saturated aqueous sodium bicarbonate solution (50 mL),
water (50 mL), and brine (50 mL). The organic phase was dried
(Na2SO4) and concentrated to give the title compound as a crystalline
pale-brown solid (2.80 g, 100%) that did not require further purification;
mp 110À111 °C (lit.,28 mp 123 °C). (Found: [M + Na+], 295.9899.
νmax (CHCl3)/cmÀ1 3429, 3011, 2982, 1723, 1603, 1529, 1480, 1239,
1157, 1051. δH (400 MHz; CDCl3) 7.83 (1 H, br s), 7.12 (1 H, br), 6.78
(1 H, d, J 8.9), 6.51 (1 H, dd, J 3.0, 8.9) 3.84 (3 H, s), 3.80 (3 H, s), 1.55
(9 H, s). δC (100 MHz; CDCl3) 154.1 (C), 152.6 (C), 141.7 (C), 128.9
(C), 110.8 (CH), 107.1 (CH), 104.3 (CH), 80.3 (C), 56.2 (Me), 55.8
(Me), 28.4 (Me).
N-(2,5-Dimethoxyphenyl)benzamide
+
C10H1279BrNNaO3 requires 295.9893.) νmax (CHCl3)/cmÀ1 3425,
3008, 1689, 1518, 1397, 1243, 1036. δH (400 MHz; CDCl3) 8.23 (1 H,
s), 7.77 (1 H, br s), 7.04 (1 H, s), 3.87 (3 H, s), 3.84 (3 H, s), 2.21 (3 H,
s). δC (75 MHz; CDCl3) 168.3 (C), 150.1 (C), 141.9 (C), 127.7 (C),
114.9 (CH), 104.6 (CH), 103.8 (C), 56.8 (Me), 56.4 (Me), 25.0 (Me).
13C Spectrum matches that reported (1H not reported).13
Benzoyl chloride (2.74 mL, 23.50 mmol) was added dropwise to 2,5-
dimethoxyaniline (3.0 g, 19.58 mmol) and triethylamine (3.26 mL,
23.50 mmol) in dichloromethane (40 mL) at 0 °C. The brown solution
was stirred for 1 h, warming to rt, then washed with saturated aqueous
sodium hydrogen carbonate solution (50 mL), hydrochloric acid
(1 M; 20 mL), and water (50 mL). The organic phase was dried
(Na2SO4) and concentrated to give a gray solid that was purified by flash
column chromatography on silica gel, eluting with ethyl acetateÀlight
petroleum (1:9À1:3) to give the title compound as off-white solid
(4.60 g, 92%); mp 84À85 °C (lit.,26 mp 82À84 °C). (Found: C, 69.8; H,
5.9; N, 5.7%. C15H15NO3 requires C, 70.0; H, 5.9; N, 5.4%.) (Found:
tert-Butyl 4-Chloro-2,5-dimethoxyphenylcarbamate
Di-tert-butyl dicarbonate (4.19 g, 19.19 mmol) was added to 4-chloro-
2,5-dimethoxyaniline (3.0 g, 15.99 mmol) in THF (15 mL), and the
resulting solution was heated to reflux and stirred for 16 h and then
cooled to rt and concentrated. The residue was purified by flash column
chromatography on silica gel eluting with ethyl acetateÀlight petroleum
(1:9) to give the title compound as an off-white crystalline solid
(3.87 g, 94%); mp 101À102 °C. (Found: C, 54.1; H, 6.3; N, 4.8%.
C13H18ClNO4 requires C, 54.3; H, 6.3; N, 4.9%). (Found: [M + Na+],
+
[M + Na+], 280.0950. C15H15NNaO3 requires 280.0944.) νmax
(CHCl3)/cmÀ1 3426, 3011, 2888, 1673, 1602, 1531, 1478, 1426,
1045. δH (400 MHz; CDCl3) 8.61 (1 H, br s), 8.32 (1 H, d, J 3.0),
7.93À7.91 (2 H, m), 7.58À7.51 (3 H, m), 6.86 (1 H, d, J 8.8), 6.65 (1 H,
dd, J 3.0, 8.8), 3.92 (3 H, s), 3.85 (3 H, s). δC (100 MHz; CDCl3) 165.2
(C), 154.0 (C), 142.4 (C), 135.2 (C), 131.8 (CH), 128.9 (CH), 128.5
(C), 127.0 (CH), 110.8 (CH), 108.9 (CH), 105.9 (CH), 56.4 (Me),
55.9 (Me).
+
310.0825. C13H1835ClNNaO4 requires 310.0817.) νmax (CHCl3)/
cmÀ1 3429, 3010, 1721, 1598, 1521, 1481, 1403, 1369, 1241, 1154,
1069, 1039. δH (400 MHz; CDCl3) 7.83 (1 H, br s), 7.36 (1 H, s), 6.88
7876
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
(1 H, s), 3.92 (3 H, s), 3.85 (3 H, s), 1.55 (9 H, s). δC (100 MHz;
CDCl3) 152.5 (C), 149.3 (C), 141.5 (C), 127.6 (C), 114.1 (C), 112.3
(CH), 103.3 (CH), 80.7 (C), 56.7 (Me), 56.4 (Me), 28.1 (Me).
N-(4-Chloro-2,5-dimethoxyphenyl)benzamide
2-tert-Butoxycarbonylamino-1,4-benzoquinone (11)
Diacetoxyiodobenzene (805 mg, 2.5 mmol) was added to tert-butyl 2,5-
dimethoxyphenylcarbamate (253 mg, 1.0 mmol) in water (5 mL)À
MeOH (125 μL). The resulting suspension was stirred for 2 h and then
diluted with water (15 mL) and extracted with dichloromethane (3 Â
10 mL). The combined extracts were washed with water (30 mL), dried
(Na2SO4), and concentrated, and the residue was purified by flash
column chromatography on silica gel, eluting with ethyl acetateÀlight
petroleum (5:95) to give the title compound as a yellow solid (130 mg,
58%); mp 91À92 °C. (Found: C, 59.0; H, 5.8; N, 6.1%. C11H13NO4
requires C, 59.2; H, 5.9; N, 6.3%.) (Found: [M + Na+], 246.0737.
C11H13NNaO4+ requires 246.0737.) νmax (CHCl3)/cmÀ1 3378, 3012,
1739, 1671, 1507, 1342, 1145, 1019. λmax (CH2Cl2)/nm 216 (log ε
4.05), 257 (3.88), 388 (3.16). δH (400 MHz; CDCl3) 7.42 (1 H, br s),
7.22 (1 H, d, J 2.4), 6.76 (1 H, d, J 10.2), 6.73 (1 H, dd, J 10.2, 2.5) 1.53
(9 H, s). δC (100 MHz; CDCl3) 187.4 (C), 182.4 (C), 151.1 (C), 139.3
(C), 138.2 (CH), 133.1 (CH), 112.5 (CH), 82.7 (C), 28.1 (Me).
2-Benzamido-1,4-benzoquinone (12)
Benzoyl chloride (2.23 mL, 19.19 mmol) was added dropwise to
4-chloro-2,5-dimethoxyaniline (3.0 g, 15.99 mmol) and triethylamine
(2.7 mL, 19.19 mmol) in dichloromethane (50 mL) at 0 °C. The brown
solution was stirred for 1 h, warming to rt, then washed with saturated
aqueous sodium hydrogen carbonate solution (50 mL), hydrochloric
acid (1 M; 20 mL), and water (50 mL). The organic phase was dried
(Na2SO4) and concentrated to give the title compound as a gray solid
(4.06 g, 87%) that did not require further purification; mp 97À98 °C.
(Found: C, 61.7; H, 5.0; N, 4.8%. C15H14ClNO3 requires C, 61.8; H,
+
4.8; N, 4.8%.) (Found: [M + Na+], 314.0550. C15H1435ClNNaO3
requires 314.0554.) νmax (CHCl3)/cmÀ1 3427, 3011, 1673, 1597, 1522,
1480, 1402, 1261, 1038. δH (400 MHz; CDCl3) 8.56 (1 H, br s), 8.54
(1 H, s), 7.92À7.89 (2 H, m), 7.60À7.51 (3 H, m), 6.97 (1 H, s). δC
(100 MHz; CDCl3) 165.3 (C), 149.2 (C), 142.2 (C), 134.8 (C), 132.0
(CH), 128.9 (CH), 127.1 (C), 127.0 (CH), 115.9 (C), 112.3 (CH),
104.9 (CH), 56.8 (Me), 56.5 (Me).
Quinones. General Procedure for Oxidation. Diacetoxyiodoben-
zene or bis(trifluoroacetoxy)iodobenzene (1.2À2.5 mmol) was added
to a stirred suspension of the protected dimethoxyaniline derivative
(1 mmol) in water (5 mL) and MeOH (125 μL). The resulting
suspension was stirred for the indicated time and then diluted with
water (15 mL) and extracted with dichloromethane (3 Â 10 mL). The
combined extracts were washed with water, dried (Na2SO4), and
concentrated, and the residue was purified by flash column chromatog-
raphy to give the protected aminobenzoquinone.
Diacetoxyiodobenzene (805 mg, 2.5 mmol) was added to N-(2,5-
dimethoxyphenyl)benzamide (257 mg, 1.0 mmol) in waterÀMeOH
(125 μL). The resulting suspension was stirred for 2 h and then diluted
with water (10 mL) and extracted with dichloromethane (3 Â 10 mL).
The combined extracts were washed with water (30 mL), dried
(Na2SO4), and concentrated, and the residue was purified by flash
column chromatography on silica gel, eluting with ethyl acetateÀlight
petroleum (1:3À1:2) to give the title compound as a yellow solid
(170 mg, 75%); mp 109À110 °C. (Found: [M + Na+], 250.0473
2-Acetamido-1,4-benzoquinone (9)
+
C13H9NNaO3 requires 250.0475.) νmax (CHCl3)/cmÀ1 3378, 3011,
1668, 1658, 1511, 1490, 1327, 1240, 1100. λmax (CH2Cl2)/nm 198 (log ε
3.85), 254 (3.62), 386 (2.74). δH (400 MHz; CDCl3) 8.86 (1 H, br s),
7.92À7.89 (2 H, m), 7.78 (1 H, d, J 2.5), 7.66À7.61 (1 H, m), 7.58À7.51
(2 H, m), 6.86 (1 H, d, J 10.2), 6.80 (1 H, dd, J 10.2, 2.5). δC (100 MHz;
CDCl3) 187.9 (C), 182.9(C), 165.8 (C), 138.43 (C), 138.40 (CH), 133.2
(CH), 133.1 (CH), 129.1 (CH), 128.8 (C), 127.3 (CH), 114.9 (CH).
2-Acetamido-5-chloro-1,4-benzoquinone (13)
Diacetoxyiodobenzene (483 mg, 1.5 mmol) was added to 2,5-
dimethoxyacetanilide (195 mg, 1.0 mmol) in water (5 mL)ÀMeOH
(125 μL). The resulting suspension was stirred for 2 h then diluted with
water (15 mL) and extracted with dichloromethane (3 Â 10 mL). The
combined extracts were washed with water (30 mL), saturated aqueous
sodium hydrogen carbonate solution (30 mL), dried (Na2SO4), and
concentrated. The residue was purified by flash column chromatography
on silica gel, eluting with ethyl acetateÀtoluene (1: 2) to give the title
compound as a golden-yellow solid (121 mg, 73%); mp 145À146 °C,
(lit.,29 mp 146À148 °C). (Found: C, 58.1; H, 4.3; N, 8.4%. C8H7NO3
requires C, 58.2; H, 4.3; N, 8.5%.) (Found: [M + Na+], 188.0318.
Bis(trifluoroacetoxy)iodobenzene (483 mg, 1.5 mmol) was added to
4-chloro-2,5-dimethoxyacetanilide (230 mg, 1.0 mmol) in water
(5 mL)ÀMeOH (125 μL). The resulting suspension was stirred for
2 h and then diluted with water (15 mL) and extracted with dichlor-
omethane (3 Â 10 mL). The combined extracts were washed with
water (30 mL), dried (Na2SO4), and concentrated, and the residue
was purified by flash column chromatography on silica gel, eluting with
ethyl acetateÀtoluene (1:2) to give the title compound as a golden-
yellow solid (146 mg, 68%); mp 183À185 °C (lit.,30 mp 168À169 °C).
(Found: C, 48.0; H, 3.0; N, 6.8%. C8H6ClNO3 requires C, 48.1; H, 3.0;
+
C8H7NNaO3 requires 188.0318.) νmax (CHCl3)/cmÀ1 3375, 3011,
1718, 1673, 1659, 1578, 1506, 1324, 1096. δH (400 MHz; acetone-d6)
8.92 (1 H, br s), 7.51 (1 H, d, J 2.3), 6.88 (1 H, d, J 10.0), 6.76 (1 H, dd,
J 10.0, 2.3), 2.29 (3 H, s). δC (100 MHz; acetone-d6) 188.1 (C), 182.6
(C), 170.3 (C), 139.5 (C), 137.5 (CH), 133.8 (CH), 113.8 (C), 23.8
(Me). NMR data matches those reported.14
This reaction was also performed on a much larger scale (10.0 g,
51.2 mmol), giving essentially the same yield of 9 (6.0 g, 71%).
7877
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
N, 7.0%.) (Found: [M + Na+], 252.0400. C8H635ClNO3 requires
252.0398.) νmax (CHCl3)/cmÀ1 3374, 1721, 1670, 1593, 1500, 1335,
1312, 1183. δH (300 MHz; CDCl3) 8.09 (1 H, br s), 7.73 (1 H, s), 7.01
(1 H, s), 2.27 (3 H, s). δC (75 MHz; CDCl3) 180.8 (C), 179.7 (C), 169.3
(C), 146.4 (C), 138.5 (C), 130.4 (CH), 114.2 (CH), 24.9 (Me).
2-Acetamido-5-bromo-1,4-benzoquinone (14)
with water (30 mL), dried (Na2SO4), and concentrated, and the residue
was purified by flash column chromatography on silica gel, eluting
with ethyl acetateÀlight petroleum (1:4) to give the title compound
as a yellow solid (165 mg, 73%); mp 148À149 °C. (Found: C, 59.4; H,
3.1; N, 5.2%. C13H8ClNO3 requires C, 59.7; H, 3.1; N, 5.4%.) (Found:
+
+
[M + Na+], 284.0096. C13H835ClNNaO3 requires 284.0085.) νmax
(CHCl3)/cmÀ1 3377, 1703, 1666, 1601, 1509, 1480, 1339, 1311, 1173,
994. λmax (CH2Cl2)/nm 201 (log ε 4.26), 273 (3.45), 426 (2.69). δH
(400 MHz; CDCl3) 8.88 (1 H, br s), 7.93À7.90 (3 H, m), 7.68À7.63
(1 H, m), 7.59À7.53 (3 H, m), 7.09 (1 H, s). δC (100 MHz; CDCl3)
181.0 (C), 179.6 (C), 165.7 (C), 146.7 (C), 138.8 (C), 133.3 (CH),
132.8 (C), 130.5 (CH), 129.2 (CH), 127.4 (CH), 114.3 (CH).
Methyl 2-Methyl-3-oxobutanoate
Bis(trifluoroacetoxy)iodobenzene (560 mg, 1.3 mmol) was added to
N-(4-bromo-2,5-dimethoxyphenyl)acetamide (244 mg, 1.0 mmol) in
water (5 mL)ÀMeOH (125 μL). The resulting suspension was stirred
for 30 min and then diluted with water (10 mL) and extracted with
dichloromethane (3 Â 10 mL). The combined extracts were washed
with water (30 mL), dried (Na2SO4), and concentrated, and the residue
was purified by flash column chromatography on silica gel, eluting
with ethyl acetateÀtoluene (1:4À3:7) to give the title compound as an
orange solid (130 mg, 53%); mp 184À185 °C (lit.,30 mp 190À192 °C).
(Found: C, 39.5; H, 2.4; N, 5.5%. C8H6BrNO3 requires C, 39.4; H, 2.5;
A mixture of methyl acetoacetate (21.6 mL, 200 mmol) and iodo-
methane (12.5 mL, 200 mmol) was cooled to 0 °C, and anhydrous
potassium carbonate (41.4 g, 300 mmol) was slowly added. The reaction
mixture was stirred at 0 °C for 2 h and then at rt overnight. Ether
(200 mL) was added, and the suspension was filtered under reduced
pressure, washing with ether (200 mL). The filtrate was washed with
brine (200 mL) and concentrated to a colorless oil that was purified by
flash column chromatography, eluting with ethyl acetateÀlight petro-
leum (1:9) to give the title compound as a colorless oil (20.3 g, 78%). δH
(300 MHz, CDCl3) 3.65 (3 H, s), 3.49 (1 H, q, J 7.3), 2.11 (3 H, s), 1.31
(3 H, d, J 7.3). δC (75 MHz; CDCl3) 203.6 (C), 171.0 (C), 53.5 (CH),
52.4 (Me), 28.5 (Me), 12.8 (Me). NMR data matched those reported.31
Methyl 2-Methyl-3-(trimethylsiloxy)but-2-enoate
+
N, 5.7%.) (Found: [M + Na+], 265.9427. C8H679BrNNaO3 requires
265.9423.) νmax (CHCl3)/cmÀ1 3374, 3012, 1721, 1668, 1593, 1503,
1331, 1167. λmax (CH2Cl2)/nm 202 (log ε 4.65), 288 (4.03), 422 (2.99).
δH (400 MHz; CDCl3) 8.05 (1 H, br s), 7.78 (1 H, s), 7.31 (1 H, s), 2.27
(3 H, s). δC (100 MHz; CDCl3) 180.4 (C), 179.7 (C), 169.2 (C), 140.6
(C), 138.4 (C), 134.7 (CH), 114.0 (CH), 24.9 (Me).
2-tert-Butoxycarbonylamino-5-chloro-1,4-benzoquinone (15)
Bis(trifluoroacetoxy)iodobenzene (645 mg, 1.5 mmol) was added to
tert-butyl 4-chloro-2,5-dimethoxyphenylcarbamate (258 mg, 1.0 mmol)
in water (5 mL)ÀMeOH (125 μL). The resulting suspension was stirred
for the indicated time and then diluted with water (15 mL) and extracted
with dichloromethane (3 Â 10 mL). The combined extracts were
washed with water (30 mL), dried (Na2SO4), and concentrated, and
the residue was purified by flash column chromatography on silica gel,
eluting with ethyl acetateÀtoluene (1:9) to give the title compound as a
golden-yellow solid (174 mg, 66%); mp 92À93 °C. (Found: C, 51.3; H,
4.7; N, 5.3%. C11H12ClNO4 requires C, 51.3; H, 4.7; N, 5.4%.) (Found:
A solution of methyl 2-methyl-3-oxobutenoate (7.0 g, 53.8 mmol) and
imidazole (550 mg, 8.1 mmol) in hexamethyldisilazane (12.5 mL,
59.2 mmol) was heated to 100 °C and stirred at this temperature for
2 h and then cooled to rt and stirred overnight. Distillation under
reduced pressure (water aspirator) gave the title compound as a color-
less oil (10.2 g, 93%); bp 140À145 °C (lit.,21 bp 60À62 °C/0.6 mmHg).
(Found: [M + H+], 203.1089. C9H19O3Si requires 203.1098.) νmax
(CHCl3)/cmÀ1 3581, 3308, 1739, 1662, 1631, 1586, 1427, 1398, 1368,
1255, 1098. δH (400 MHz; CDCl3) 3.71 (3 H, s), 2.29 (3 H, d, J 1.2),
1.78 (3 H, d, J 1.2), (9 H, s). δC (100 MHz; CDCl3) 170.2 (C), 161.7
(C), 108.8 (C), 51.1 (Me), 21.6 (Me), 12.4 (Me), 0.5 (Me).
+
[M + Na+], 280.0358. C11H1235ClNNaO4 requires 280.0347.) νmax
(CHCl3)/cmÀ1 3378, 2984, 1739, 1671, 1506, 1145, 1019. λmax
(CH2Cl2)/nm 223 (log ε 4.75), 280 (4.68), 406 (3.70). δH (300
MHz; CDCl3) 7.43 (1 H, br s), 7.35 (1 H, s), 6.98 (1 H, s), 1.53 (9
H, s). δC (75 MHz; CDCl3) 184.5 (C), 179.1 (C), 150.8 (C), 146.4 (C),
139.7 (C), 130.4 (CH), 111.9 (CH), 83.1 (C), 28.0 (Me).
1-Methoxy-2-methyl-1,3-bis(trimethylsiloxy)-1,3-butadiene (19)
2-Benzamido-5-chloro-1,4-benzoquinone (16)
n-Butyllithium (2.5 M in hexanes; 35 mL, 89.0 mmol) was added to
a solution of diisopropylamine in THF (175 mL) at 0 °C. The solution
was warmed to rt, stirred for 5 min, and then cooled to À78 °C.
Chlorotrimethylsilane (13.8 mL, 108.7 mmol) was added, followed by
a solution of methyl 2-methyl-3-(trimethylsiloxy)but-2-enoate (10.0 g,
49.4 mmol) in THF (15 mL). The reaction mixture was stirred at
À78 °C for 1 h, then warmed to rt over 30 min. Solvents were removed
in vacuo at rt, and dry n-pentane (150 mL) was added. The resulting
suspension was filtered repeatedly until no salts remained, then
Bis(trifluoroacetoxy)iodobenzene (645 mg, 1.5 mmol) was added to
N-(4-chloro-2,5-dimethoxyphenyl)benzamide (292 mg, 1.0 mmol) in
water (5 mL)ÀMeOH (125 μL). The resulting suspension was stirred
for 2 h and then diluted with water (10 mL) and extracted with
dichloromethane (3 Â 10 mL). The combined extracts were washed
7878
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
concentrated in vacuo to give a pale-yellow oil (14 g, >100%) that was
not purified further and was stored in the freezer. δH (300 MHz; CDCl3)
4.42 (1 H, s), 4.29 (1 H, s), 3.56 (3 H, s), 1.65 (3 H, s), 0.24 (9 H, s) 0.20
(9 H, s). NMR data matches those reported.21
2-tert-Butoxycarbonylamino-6-hydroxy-8-methoxy-7-methyl-1,4-
naphthoquinone (20)
2.0 mmol) in toluene (5 mL). The green solution was stirred at room
temperature for 2 h and then poured into hydrochloric acid (1 M;
15 mL) and ethyl acetate (10 mL). The layers were separated, and the
aqueous phase was extracted with ethyl acetate (2 Â 10 mL). Silica gel
(ca. 5 g) was added to the combined extracts and the suspension stirred
under air at rt for 24 h. Concentration and flash column chromatography
eluting with ethyl acetateÀtoluene (1:2) gave the title compound as
an orange powder (137 mg, 43%); mp >300 °C decomp. (Found: [M +
+
Na+], 342.0938. C16H17NNaO6 requires 342.0948.) νmax (CHCl3)/
cmÀ1 3691, 1605, 3376, 3001, 1736, 1632, 1603, 1507, 1325, 1150,
1054, 1029, 1011. λmax (CH2Cl2)/nm 224 (log ε 4.21), 263 (3.81), 318
(3.78), 449 (3.38). δH (400 MHz; DMSO-d6) 12.81 (1 H), 11.00 (1 H,
s), 8.73 (1 H, s), 7.12 (1 H, s), 7.10 (1 H, s), 2.06 (3 H, s), 1.50 (9 H, s).
δC (100 MHz; DMSO-d6) 189.9 (C), 179.7 (C), 161.8 (C), 161.2
(C), 152.1 (C), 142.8 (C), 129.1 (C), 126.9 (C), 118.7 (C),
114.1 (CH), 107.9 (CH), 82.3 (C), 28.2 (Me), 9.2 (Me). A small
amount of the 8-methoxy-6-hydroxy- compound (30 mg, 9%) was also
formed.
1-Methoxy-2-methyl-1,3-bis(trimethylsiloxy)-1,3-butadiene (19)
(565 mg, 2.0 mmol) was added dropwise to 2-tert-butoxycarbonyla-
mino-1,4-benzoquinone (11) (223 mg, 1.0 mmol) in toluene (5 mL).
The green solution was stirred at room temperature for 2 h and then
poured into hydrochloric acid (1 M; 15 mL) and ethyl acetate (10 mL).
The layers were separated, and the aqueous phase was extracted with ethyl
acetate (2 Â 10 mL). Silica (ca. 5 g) was added to the combined extracts
and the suspension stirred under air at rt for 24 h. Concentration and flash
column chromatography eluting with ethyl acetateÀtoluene (1:2) gave the
title compound, which was recrystallized from toluene to give a yellow
powder (212 mg, 64%); mp >280 °C decomp. (Found: [M + Na+],
356.1103. C17H19NNaO6+ requires 356.1105.) νmax (CHCl3)/cmÀ1 3582,
3367, 3008, 1737, 1662, 1582, 1501, 1313, 1149, 1111. λmax (CH2Cl2)/nm
219 (log ε 4.22), 272 (4.10), 314 (4.01). δH (300 MHz; DMSO-d6) 11.18
(1 H, br s), 8.44 (1 H, s), 7.25 (1 H, s), 7.07 (1 H, s), 3.71 (3 H, s), 2.09
(3 H, s), 1.49 (9 H, s). δC (75 MHz; DMSO-d6) 184.4 (C), 177.1 (C),
162.8 (C), 161.0 (C), 151.9 (C), 143.0 (C), 132.9 (C), 124.7 (C), 115.1
(C), 112.3 (CH), 109.0 (CH), 82.1 (C), 60.9 (Me), 28.2 (Me), 9.2 (Me).
2-Amino-6,8-dihydroxy-7-methyl-1,4-naphthoquinone (17)
3-Amino-6,8-dihydroxy-7-methyl-1,4-naphthoquinone (22)
Magnesium bromide (276 mg, 1.5 mmol) was added to a solution of
3-tert-butoxycarbonylamino-6,8-dihydroxy7-methyl-1,4-naphthoquinone
(21) (20 mg, 0.06 mmol) in toluene (5 mL), and the mixture was heated
to reflux and stirred for 18 h. The reaction mixture was poured into
hydrochloric acid (1 M; 5 mL) and extracted with ethyl acetate (3 Â
5 mL). The combined extracts were washed with water (10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated. The residue was purified
by flash column chromatography on silica gel eluting with ethyl acetateÀ
toluene (1:2) to give a dark-red powder (11 mg, 80%); mp >300 °C
decomp. (Found: [M À H+], 218.0455. C11H8NO4À requires 218.0459.)
νmax (ATR)/cmÀ1 3432, 3337, 3291, 1609, 1567, 1480, 1386, 1354, 1308,
1262, 1105. λmax (CH2Cl2)/nm 210 (log ε 3.93), 224 (3.83), 270 (3.88),
338 (3.55), 399 (3.05). δH (400 MHz; DMSO-d6) 13.71 (1 H, s), 10.57
(1 H, br s), 7.33 (1 H, br s), 7.07 (1 H, s), 5.64 (1 H, s), 2.03 (3 H, s).
δC (100 MHz; DMSO-d6) 188.7 (C), 181.8 (C), 160.9 (C), 160.2 (C),
151.5 (C), 129.1 (C), 119.0 (C), 107.6 (C), 106.8 (CH), 100.7 (CH),
8.7 (Me).
Magnesium bromide (276 mg, 1.5 mmol) was added to a solution of
2-tert-butoxycarbonylamino-6-hydroxy-8-methoxy-7-methyl-1,4-
naphthoquinone (20) (50 mg, 0.15 mmol) in toluene (10 mL), and the
mixture was heated to reflux and stirred for 18 h. The reaction mixture
was poured into hydrochloric acid (1 M; 5 mL) and extracted with
ethyl acetate (3 Â 5 mL). The combined extracts were washed with
water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated
to give the title compound as a red powder (33 mg, 99%) that did not
require further purification; mp >300 °C decomp. (Found: [M + Na+],
1-(2-Methyl-1,3-dioxolan-2-yl)propan-2-one
+
242.0430. C11H9NNaO4 requires 242.0424.) νmax (CHCl3)/cmÀ1
3464, 3349, 1598, 1563, 1326, 1273, 1127, 1072. λmax (CH2Cl2)/nm
225 (log ε 4.72), 267 (3.67), 275 (3.65), 341 (3.62). δH (400 MHz;
DMSO-d6) 12.22 (1 H, s), 11.15 (1 H, br s), 7.21 (1 H, br s), 7.00 (1 H,
s), 5.66 (1 H, s), 2.02 (3 H, s). δC (100 MHz; DMSO-d6) 184.6 (C),
181.4 (C), 163.9 (C), 162.2 (C), 151.3 (C), 133.1 (C), 114.2 (C), 107.6
(C), 107.3 (CH), 102.0 (CH), 8.2 (Me).
p-Toluenesulfonic acid (43 mg, 0.23 mmol) was added to a solution of
acetylacetone (20.0 g, 200 mmol) and ethylene glycol (14.2 g, 200
mmol) in benzene (40 mL). The mixture was heated to reflux, and the
solution was stirred overnight with azeotropic removal of water using
a DeanÀStark trap. Benzene was carefully removed under reduced
pressure, and the remaining liquid was fractionally distilled twice
through a 30 cm Vigreux column under reduced pressure (water
aspirator). The title compound (19.1 g, 66%) was obtained along with
some minor impurities which did not affect subsequent reactions; bp
122À124 °C/5 mmHg (lit.,23 bp 120 °C/5 mmHg). νmax (CHCl3)/
cmÀ1 2989, 2888, 1709, 1790, 1361, 1241, 1054. δH (400 MHz; CDCl3)
3.97À3.94 (4 H, m), 2.75 (2 H, s), 2.20 (3 H, s), 1.39 (3 H, s). δC (100
MHz; CDCl3) 205.9 (C), 107.8 (C), 64.6 (CH2), 64.2 (CH2), 52.5
(CH2), 31.6 (Me), 24.3 (Me).
3-tert-Butoxycarbonylamino-6,8-dihydroxy7-methyl-1,4-naphtho-
quinone (21)
1-Methoxy-2-methyl-1,3-bis(trimethylsiloxy)-1,3-butadiene (19) (564
mg, 2.0 mmol) was added dropwise to 2-chloro-5-tert-butoxycarbonylami-
no-1,4-benzoquinone (15) (258 mg, 1.0 mmol) and pyridine (160 μL,
7879
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
Methyl 3-Methyl-4-(2-methyl-1,3-dioxolan-2-yl)but-2-enoate (23)
2-tert-butoxycarbonylamino-1,4-benzoquinone (11) (223mg, 1.0 mmol)
in dichloromethane (10 mL). The green solution was stirred at rt for 2 h
and then poured into hydrochloric acid (1 M; 15 mL) and ethyl acetate
(10 mL). The layers were separated, and the aqueous phase was extracted
with ethyl acetate (2 Â 10 mL). The combined organic extracts were
treated with silica gel (ca. 5 g), and the suspension stirred under air for
16 h. Concentration and flash column chromatography on silica gel
eluting with ethyl acetateÀtoluene (1:9À1:4) gave the title compound as
an orange powder (250 mg, 64%); mp 120À121 °C. (Found: [M + Na+],
Sodium hydride (60% in mineral oil; 8.32 g, 208.1 mmol) was washed
with dry n-pentane (30 mL), dried under vacuum, suspended in THF
(250 mL), and cooled to 0 °C. Methyl diethyl phosphonoacetate
(38.2 mL, 208.1 mmol) was added dropwise, and the reaction mixture
was slowly heated to reflux. 1-(2-Methyl-1,3-dioxolan-2-yl)propan-2-
one (20.0 g, 138.7 mmol) in THF (50 mL) was added dropwise and the
suspension stirred for 6 h then cooled to rt. Ether (100 mL) and brine
(200 mL) were added, and the aqueous phase was extracted with ether
(3 Â 100 mL). The combined ethereal extracts were washed with water
(2 Â 200 mL) and brine (2 Â 200 mL), dried, and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography on silica gel eluting with etherÀlight petroleum (1:25)
to give the title compound as a colorless oil (20.2 g, 73%) as a 2.2:1
mixture of geometric isomers which were used directly in the next
reaction. νmax (CHCl3)/cmÀ1 2989, 2952, 2888, 1712, 1646, 1437,
1380, 1155, 1055. Major: δH (400 MHz; CDCl3) 5.78 (1 H, d, J 0.7),
3.96À3.94 (4 H, m), 3.71 (3 H, s), 2.48 (2 H, s), 2.26 (3 H, d, J 1.5), 1.34
(3 H, s); δC (100 MHz; CDCl3) 166.9 (C), 155.5 (C), 119.2 (CH),
109.4 (C), 64.7 (CH2), 50.8 (Me), 49.5 (CH2), 24.3 (Me), 20.1 (Me).
Minor: δH (400 MHz; CDCl3) 5.81 (1 H, d, J 0.7), 3.96À3.94 (4 H, m),
3.70 (3 H, s), 3.10 (2 H, s) 2.00 (3 H, d, J 1.5), 1.36 (3 H, s); δC (100
MHz; CDCl3) 166.8 (C), 154.9 (C), 118.8 (CH), 109.9 (C), 64.5
(CH2), 50.8 (Me), 41.1 (CH2), 26.5 (Me), 24.0 (Me).
+
412.1356. C20H23NNaO7 requires 412.1367.) νmax (CHCl3)/cmÀ1
3381, 3011, 1736, 1639, 1614, 1506, 1383, 1294, 1148, 1049. λmax
(CH2Cl2)/nm 211 (log ε 5.06), 228 (4.09), 304 (3.75), 409 (3.30). δH
(400 MHz; CDCl3) 11.38 (1 H, s), 7.69 (1 H, br s), 7.55 (1 H, d, J 1.6),
7.42 (1 H, s), 7.15 (1 H, d, J 1.6), 3.92À3.90 (2 H, m), 3.84À3.82 (2 H,
m), 2.98 (2 H, s), 1.55 (9 H, s), 1.33 (3 H, s). δC (100 MHz; CDCl3)
184.4 (C), 184.1 (C), 161.4 (C), 151.1 (C), 148.6 (C), 140.9 (C), 138.7
(C), 124.7 (CH), 121.8 (CH), 115.5 (CH), 112.2 (C), 109.1 (C), 82.7
(C), 64.9 (CH2), 44.6 (CH2), 28.1 (Me), 24.5 (Me).
3-tert-Butoxycarbonylamino-8-hydroxy-6-[(2-methyl-1,3-dioxo-
lan-2-yl)methyl]-1,4-naphthoquinone (26)
. 1-Methoxy-3-((2-methyl-1,3-dioxolan-2-yl)methyl)buta-1,3-dienylox-
ytrimethylsilane (24) (410 mg, 1.5 mmol) was added dropwise to
5-chloro-2-tert-butoxycarbonylamino-1,4-benzoquinone (15) (258 mg,
1.0 mmol) and pyridine (160 μL, 2.0 mmol) in dichloromethane
(10 mL). The green solution was stirred at rt for 4 h and then silica
gel (ca. 5 g) was added, and the suspension stirred under air for 16 h.
Concentration and flash column chromatography on silica gel eluting
with ethyl acetateÀtoluene (1:9À1:4) gave the title compound as an
orange powder, which was recrystallized from tolueneÀhexane (ca. 1:2)
to give red crystals (193 mg, 49%); mp 135À137 °C. (Found: C, 61.7; H,
5.9; N, 3.5%. C20H23NO7 requires C, 61.7; H, 6.0; N, 3.6%.) (Found: [M
+ Na+], 412.1358. C20H23NNaO7+ requires 412.1367.) νmax (CHCl3)/
cmÀ1 3373, 2986, 1738, 1673, 1635, 1613, 1504, 1372, 1325, 1278, 1150.
λmax (CH2Cl2)/nm 210 (log ε 4.23), 252 (4.02), 304 (4.81), 436 (3.55).
δH (400 MHz; CDCl3) 12.32 (1 H, s), 7.78 (1 H, br s), 7.57 (1 H, d,
J 1.6), 7.39 (1 H, s), 7.23 (1 H, d, J 1.6), 3.95À3.92 (2 H, m), 3.82À3.80
(2 H, m), 2.98 (2 H, s), 1.56 (9 H, s), 1.35 (3 H, s). δC (100 MHz;
CDCl3) 190.5 (C), 180.1 (C), 160.9 (C), 151.1 (C), 145.6 (C), 141.7
(C), 129.4 (C), 127.4 (CH), 121.9 (CH), 114.3 (CH), 112.2 (C), 109.2
(C), 82.8 (C), 64.9 (CH2), 45.4 (CH2), 28.0 (Me), 24.3 (Me).
3-Acetamido-8-hydroxy-6-[(2-methyl-1,3-dioxolan-2-yl)methyl]-
1,4-naphthoquinone (27)
1-Methoxy-3-[(2-methyl-1,3-dioxolan-2-yl)methyl]buta-1,3-dienyl-
oxytrimethylsilane (24)
n-Butyllithium (2.5 M in hexanes; 52.0 mL, 129.9 mmol) was added to a
0 °C solution of diisopropylamine (18.3 mL, 129.9 mmol) in THF
(300 mL). The solution was warmed to rt, stirred for 5 min, and then
cooled to À78 °C. Chlorotrimethylsilane (20.3 mL, 159.8 mmol) was
added, followed by dropwise addition of methyl 3-methyl-4-(2-methyl-
1,3-dioxolan-2-yl)but-2-enoate (23) (20.0 g, 99.9 mmol) in THF
(30 mL). The resulting solution was stirred at À78 °C for 90 min and
then warmed to rt and concentrated without heating in vacuo. The
residue was diluted with dry n-pentane (50 mL) and careful filtration
under nitrogen followed by concentration gave the title compound as a
colorless oil (27.0 g, quant.) that was used without further purification,
and stored in the freezer. (Found [M + Na+] 295.1322. C13H24NaO4Si+
requires 295.1336.) νmax (CHCl3)/cmÀ1 3011, 2962, 2888, 1707, 1646,
1598, 1254, 1097, 1050, 976. δH (400 MHz; CDCl3) 5.26 (1 H, d, J 2.5),
4.81 (1 H, d, J 2.5), 4.24 (1 H, s), 3.97À3.95 (4 H, m), 3.58 (3 H, s), 2.50
(2 H, s), 1.37 (3 H, s), 0.26 (9 H, s). δC (100 MHz; CDCl3) 157.7 (C),
138.3 (C), 110.9 (CH2), 110.2 (C), 79.2 (CH), 64.4 (CH2), 55.0 (CH),
47.3 (CH2), 23.8 (Me), 0.5 (Me).
2-tert-Butoxycarbonylamino-8-hydroxy-6-[(2-methyl-1,3-dioxo-
lan-2-yl)methyl]-1,4-naphthoquinone (25)
1-Methoxy-3-((2-methyl-1,3-dioxolan-2-yl)methyl)buta-1,3-dienyloxy-
trimethylsilane (24) (220 mg, 0.81 mmol) was added dropwise to
2-acetamido-5-chloro-1,4-benzoquinone (13) (100 mg, 0.54 mmol) in
dichloromethane (5 mL). The solution was stirred at rt for 2 h, and then
silica gel (ca. 3 g) was added and the resulting suspension was stirred
for 18 h under air. Concentration and flash column chromatography
on silica gel eluting with ethyl acetateÀtoluene (1:2À1:1), followed by
recrystallization from tolueneÀhexane (ca. 1:1), gave the product as an
orangeÀbrown solid (97 mg, 54%); mp 164À165 °C. (Found: C, 61.4;
1-Methoxy-3-((2-methyl-1,3-dioxolan-2-yl)methyl)buta-1,3-dienyloxy-
trimethylsilane (24) (410 mg, 1.5 mmol) was added dropwise to
7880
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881

The Journal of Organic Chemistry
ARTICLE
H, 5.2; N, 4.1%. C17H17NO6 requires C, 61.6; H, 5.2; N, 4.2%.) (Found:
(20) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y. L.; Sugita,
K.; Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202–206.
(21) Courchesne, M.; Brassard, P. J. Nat. Prod. 1993, 56, 722–730.
(22) Boisvert, L.; Brassard, P. J. Org. Chem. 1988, 53, 4052–4059.
(23) Vela, J.; Zhu, L. W.; Flaschenriem, C. J.; Brennessel, W. W.;
Lachicotte, R. J.; Holland, P. L. Organometallics 2007, 26, 3416–3423.
(24) Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzman, S. W.;
Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.; Stevens, J. E.
J. Org. Chem. 1991, 56, 91–95.
(25) Gould, S. J.; Shen, B.; Whittle, Y. G. J. Am. Chem. Soc. 1989,
111, 7932–7938.
(26) Lyon, M. A.; Lawrence, S.; Williams, D. J.; Jackson, Y. A.
J. Chem. Soc., Perkin Trans. 1 1999, 437–442.
+
[M + Na+], 354.0948. C17H17NNaO6 requires 354.0948.) νmax
(CHCl3)/cmÀ1 3368, 2989, 2888, 1717, 1670, 1637, 1612, 1503,
1382, 1319, 1277, 1047. λmax (CH2Cl2)/nm 212 (log ε 4.07), 253
(3.86), 302 (3.66), 435 (3.39). δH (400 MHz; CDCl3) 12.26 (1 H, s),
8.41 (1 H, br s), 7.80 (1 H, s), 7.61 (1 H, d, J 1.7), 7.27 (1 H, d, J 1.7),
3.98À3.94 (2 H, m), 3.83À3.79 (2 H, m), 3.01 (2 H, s), 2.31 (3 H, s),
1.37 (3 H, s). δC (100 MHz; CDCl3) 191.1 (C), 180.4 (C), 169.5 (C),
160.9 (C), 146.0 (C), 140.5 (C), 129.2 (C), 127.6 (CH), 122.3 (CH),
116.7 (CH), 112.7 (C), 109.1 (C), 65.0 (CH2), 45.5 (CH2), 25.1 (Me),
24.6 (Me).
(27) Bloom, A. U.S. Patent 2649482, 1953.
(28) Gulland, J. M.; Robinson, R.; Scott, J.; Thornley, S. J. Chem. Soc.
’ ASSOCIATED CONTENT
1929, 2924–2941.
1
Supporting Information. Copies of H and 13C NMR
S
b
(29) Buttrus, N. H.; Cornforth, J.; Hitchcock, P. B.; Kumar, A.;
Stuart, A. S. J. Chem. Soc., Perkin Trans. 1 1987, 851–857.
(30) Kelly, T. R.; Echavarren, A.; Behforouz, M. J. Org. Chem. 1983,
48, 3849–3851.
spectra, X-ray structure of compound 26, and associated .cif file
for the X-ray structure. This material is available free of charge via
the Internet at http://pubs.acs.org.
(31) Collins, D. J.; Choo, G. L. P.; Obrist, H. Aust. J. Chem. 1990,
43, 617–622.
’ AUTHOR INFORMATION
Corresponding Author
*c.j.moody@nottingham.ac.uk
’ ACKNOWLEDGMENT
We thank the EPSRC for funding (DTA studentship to C.C.N.).
’ REFERENCES
(1) Thomson, R. H. Naturally Occurring Quinones IV. Recent Advances,
4th ed.; Blackie: London, 1997.
(2) O’Brien, R. J.; Lyle, M. A.; Snider, D. E. Rev. Infecti. Dis. 1987,
9, 519–530.
(3) Brogden, R. N.; Fitton, A. Drugs 1994, 47, 983–1009.
(4) Matsuda, S.; Adachi, K.; Matsuo, Y.; Nukina, M.; Shizuri, Y.
J. Antibiot. 2009, 62, 519–526.
(5) Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J. J. Org. Chem.
2005, 70, 4414–4422.
(6) McErlean, C. S. P.; Moody, C. J. J. Org. Chem. 2007, 72, 10298–
10301.
(7) Coombes, C. L.; Moody, C. J. J. Org. Chem. 2008, 73, 6758–
6762.
(8) Guillonneau, L.; Taddei, D.; Moody, C. J. Org. Lett. 2008, 10,
4505–4508.
(9) Padwal, J.; Lewis, W.; Moody, C. J. Org. Biomol. Chem. 2011,
9, 3484–3493.
(10) Kulanthaivel, P.; Perun, T. J.; Belvo, M. D.; Strobel, R. J.; Paul,
D. C.; Williams, D. C. J. Antibiot. 1999, 52, 256–262.
(11) Kelly, T. R.; Behforouz, M.; Echavarren, A.; Vaya, J. Tetrahedron
Lett. 1983, 24, 2331–2334.
(12) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y. L. Angew.
Chem., Int. Ed. 2001, 40, 207–210.
(13) Whiteley, C. G. Bioorg. Med. Chem. 2002, 10, 1221–1227.
(14) Wipf, P.; Kim, Y. T.; Jahn, H. Synthesis 1995, 1549–1561.
(15) Taylor, R. J. K.; Alcaraz, L.; Kapfer-Eyer, I.; Macdonald, G.;
Wei, X. D.; Lewis, N. Synthesis 1998, 775–790.
(16) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Sugita, K. J. Am.
Chem. Soc. 2002, 124, 2212–2220.
(17) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y. L. J. Am.
Chem. Soc. 2002, 124, 2221–2232.
(18) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Barluenga, S.; Hunt,
K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233–2244.
(19) Tohma, H.; Morioka, H.; Harayama, Y.; Hashizume, M.; Kita,
Y. Tetrahedron Lett. 2001, 42, 6899–6902.
7881
dx.doi.org/10.1021/jo201320g |J. Org. Chem. 2011, 76, 7872–7881